5′‑<i>C</i>‑Ethyl-tetrazolyl‑<i>N</i>⁶‑Substituted Adenosine and 2‑Chloro-adenosine Derivatives as Highly Potent Dual Acting A₁ Adenosine Receptor Agonists and A₃ Adenosine Receptor Antagonists

A series of <i>N</i>⁶-substituted-5′-<i>C</i>-(2-ethyl-2<i>H</i>-tetrazol-5-yl)-adenosine and 2-chloro-adenosine derivatives was synthesized as novel, highly potent dual acting hA₁AR agonists and hA₃AR antagonists, potentially useful in the treatment of glaucoma and other diseases. The best affinity and selectivity profiles were achieved by <i>N</i>⁶-substitution with a 2-fluoro-4-chloro-phenyl- or a methyl- group. Through an in silico receptor-driven approach, the molecular bases of the hA₁- and hA₃AR recognition and activation of this series of 5′-<i>C</i>-ethyl-tetrazolyl derivatives were explained.